28 October 2015

Hidden gem of a finding or not?

Todays paper is from a group in Korea.  It's a typical "we did some in silico screening, limited biochemical testing, made a compound or two, and voila!" paper.  In this case, the target is Tyk2 (the target of Xeljanz).
Figure 1.  Xeljanz (tofacitinib)
2000 diverse fragments were selected from the Otava library and docked against Tyk2.  64 top ranked fragments were selected and 9 were selected that had inhibition over 50% at 100 microM, with the best compound (1) having 60% inhibition at 3 microM.  

Figure 2.  Cpd 1 docked to Tyk2. 
What I don't like here is that they didn't do full dose-response curves.  That seems lazy.  Also, the only structures they show are the docked structures.  Maybe its just me, but show me some line drawings.  They then did some limited SAR (3 cpds) based on 1 as the scaffold.  Cpd 12 was the best compound 
Figure 3.  Cpd 12
(10nM IC50).  In the end, 12 was equipotent (or superior) with tofacitinib in terms of shutting down Tyk2/Stat3 signalling.  However, they could not rule out that this is due to non-specific inhibition of other JAK proteins. So, is this a great result?  If so, why BOMCL (not to be snobby)?


Dan Erlanson said...

Looks like they only counter-screened their best compound against four other kinases, and it hit three of them.

Anonymous said...

Looks an awful lot like this: http://pubs.acs.org/doi/abs/10.1021/jm300952s
Just saying...